The HIV-1 envelope glycoproteins, gp120 and gp41, mediate viral attachment and penetration into CD4+ cells; some isolates of HIV-1, however, are restricted in their ability to infect productively primary macrophages or continuous CD4+ cell lines. In order to study the biochemical basis for these differences, a variety of infectious molecular clones of HIV-1 containing defined mutations within the envelope glycoproteins were analyzed employing radiolabeled purified virions to evaluate envelope structure and function. The tendency of purified virions to release their gp120 envelope component either spontaneously or after interacting with a soluble form of CD4 increased in parallel with the ability of different HIV-1 variants to grow in CD4+ cell lines. In contrast, both spontaneous and soluble CD4-induced release of gp120 from virions of macrophage-tropic HIV-1 variants was substantially reduced. Work is currently in progress to determine the relationship between these altered physical and functional properties and the ability of HIV-1 to infect different cell types productively. More than 90% of chimpanzees inoculated with HIV-1 have received derivatives of the HIV-1LAI/IIIB isolate. These inoculated chimps invariably become infected, produce antibodies to viral proteins, but fail to develop disease. In an attempt to develop a disease model of AIDS in HIV-1 infected chimpanzees, fresh HIV-1 isolates were screened from seropositive, symptomatic individuals for their ability to replicate in chimpanzee PBMCs. Of 23 samples freshly isolated from AIDS or ARC patients, 3 isolates (DH012, 20, and 29) could readily infect chimp PBMCs in vitro. DH012 and DH029 also readily infected human monocyte derived macrophages. DH012 replicated more rapidly and to higher titers in chimpanzee PBMCs compared to a 'chimp-adapted' derivative of HIVIIIB. HIV-1 DH012 also induced marked CPE in both human and chimpanzee PBMCs and was able to infect PBMCs from 16 different animals including a sample from a chimpanzee that had been previously inoculated and continued to be persistently infected with HIV-1IIIB. The nucleotide sequence of the V3 envelope regions of the three 'chimp-tropic' HIV-1 isolates were unremarkable. HIV-1DH012 (alone) and a mixture of the three chimp-tropic HIV-1 isolates will be used to infect chimpanzees.